Tramal^® Retard (Tablets) Instructions for Use

ATC Code

N02AX02 (Tramadol)

Active Substance

Tramadol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Opioid analgesic with a mixed mechanism of action. Extended-release drug

Pharmacotherapeutic Group

Opioid analgesic agent

Pharmacological Action

Opioid analgesic. It exerts a pronounced analgesic effect, which is due to its agonistic influence on opioid receptors in the CNS. Tramadol is a synthetic opioid, it is a racemate of (+) and (-) isomers, which participate in the analgesic action in different ways.

The (+) isomer is a pure agonist of opioid receptors, the (-) isomer inhibits neuronal norepinephrine reuptake, activates the central descending noradrenergic system, which disrupts the transmission of pain impulses to the gelatinous substance of the spinal cord; both isomers act synergistically. It causes a sedative effect.

In therapeutic doses, Tramadol practically does not affect hemodynamic parameters and does not depress respiratory function. With controlled use, habituation and drug dependence develop extremely rarely and are less pronounced compared to morphine.

From Tramal retard tablets, Tramadol enters the blood slowly but continuously, which leads to an increase in the duration of the drug’s action.

Pharmacokinetics

Absorption

After oral administration, Tramadol is rapidly absorbed from the gastrointestinal tract. C_max in blood plasma after taking retard tablets is reached in 4-5 hours, providing a sufficient effective concentration in plasma for 12 hours. Bioavailability is 68%.

Distribution

V_d after oral administration is 3 l/kg. Binding to plasma proteins is about 20%.

Tramadol penetrates the blood-brain barrier and the placental barrier; up to 0.1% is excreted in breast milk.

Metabolism

It is metabolized by N- and O-demethylation in the liver; one of the metabolites, mono-O-desmethyltramadol, has a more pronounced analgesic effect compared to tramadol.

Excretion

About 30% is excreted by the kidneys unchanged, up to 60% as metabolites and conjugates. T_1/2 of tramadol and mono-O-desmethyltramadol is 6-7 hours.

Pharmacokinetics in special clinical cases

In patients with hepatic insufficiency, T_1/2 of tramadol and mono-O-desmethyltramadol increases to 9-18 hours and 9-28 hours, respectively; in patients with renal insufficiency (creatinine clearance less than 5 ml/min) these figures are 8-14 hours and 14-20 hours, respectively. An increase in T_1/2 was noted in patients over 75 years of age.

Indications

Acute and chronic, moderate and severe pain syndrome of various etiologies (including in the elderly and patients with respiratory difficulties)

• In malignant tumors;
• In trauma;
• In neuralgias;
• In diagnostic and therapeutic procedures.

Prevention of pain syndrome in the preoperative period.

ICD codes

Dosage Regimen

Tablets

The dose is set depending on the intensity of pain and the individual sensitivity of the patient. Tramal retard is sufficient to take 2 times/day, in the morning and evening, regardless of food intake.

Adults and adolescents over 14 years of age are prescribed 100 mg (1 tablet) 2 times/day, in the morning and evening. If the analgesic effect is insufficient, the dose can be increased by taking 1 tablet of 150 mg or 200 mg, also in the morning and evening; the intervals between doses are set individually but must be at least 6 hours. The maximum dose is 400 mg/day.

In elderly patients (over 75 years of age), the elimination of the drug may be slowed. In such cases, it is necessary to increase the interval between doses according to the patient’s condition.

In renal insufficiency/dialysis and in hepatic insufficiency, the elimination of tramadol is slowed. In this category of patients, it is necessary to individually select the interval between doses of the drug according to the patient’s condition.

The tablets should be swallowed whole, without chewing, with a sufficient amount of liquid.

Tramal retard should not be used longer than therapeutically necessary.

Adverse Reactions

From the CNS dizziness, headache are possible; rarely – blurred vision, mood changes (mostly improvement, less often – dysphoria), change in activity (mostly suppression, less often – increase), perception disorders (behavioral reactions, sensory disturbances); in isolated cases – epileptiform convulsions (the risk increases mainly after prescribing tramadol in high doses, or with simultaneous use of drugs that can increase the seizure potential (i.e., antidepressants or antipsychotics).

Development of dependence and withdrawal reactions, similar to those upon withdrawal of other opioid analgesics, is possible: agitation, excitability, nervousness, insomnia, hyperkinesis, tremor, and gastrointestinal disorders.

From the digestive system nausea, vomiting, constipation are possible; rarely – abdominal pain, feeling of stomach fullness, changes in appetite; in isolated cases – increased activity of liver enzymes when taking tramadol.

From the cardiovascular system rarely – palpitation, tachycardia, hypotension, and orthostatic collapse; in isolated cases – increased blood pressure, bradycardia.

Dermatological reactions rarely – itching, rash.

From the urinary system in isolated cases – urination disorders.

Allergic reactions rarely – urticaria, respiratory distress, bronchospasm, asthmatic component, angioneurotic edema, anaphylactic reactions.

From the respiratory system worsening of the asthmatic condition is possible. Respiratory depression is sometimes noted, usually in the case of a significant excess of recommended doses or when combined with other drugs that have a depressant effect on the CNS.

Other rarely – muscle weakness.

Contraindications

• Acute poisoning with alcohol, hypnotics, analgesics, or psychotropic drugs (i.e., agents acting on the nervous system);
• Withdrawal syndrome from narcotic substances;
• Pregnancy;
• Lactation (single use for vital indications is possible);
• Children under 14 years of age;
• Simultaneous use of MAO inhibitors and the 2-week period after their withdrawal;
• Hypersensitivity to tramadol or other opioid analgesics.

Use in Pregnancy and Lactation

Tramal retard is contraindicated during pregnancy.

In cases of extreme necessity, one should limit oneself to a single dose of the drug. Tramadol, prescribed before or during childbirth, does not affect uterine contractility. In newborns, respiratory slowing may occur, which is clinically insignificant.

Tramal retard is contraindicated during lactation. About 0.1% of the dose received by the mother is excreted in breast milk. However, after taking a single dose of the drug, it is usually not necessary to interrupt breastfeeding.

Use in Hepatic Impairment

In hepatic insufficiency, the elimination of tramadol is slowed. In this category of patients, it is necessary to individually select the interval between doses of the drug according to the patient’s condition.

Use in Renal Impairment

In renal insufficiency/dialysis the elimination of tramadol is slowed. In this category of patients, it is necessary to individually select the interval between doses of the drug according to the patient’s condition.

Special Precautions

Use Tramal retard with caution in patients with drug dependence on opioid analgesics, in shock, confusion of unknown origin, respiratory disorders, with increased intracranial pressure (due to head injuries or brain diseases).

The drug is used with caution in patients with increased sensitivity to opiates.

The possibility of seizures in patients taking Tramadol at recommended doses should be considered. The risk of seizures increases when the daily dose of the drug is exceeded (400 mg). Taking tramadol may increase the risk of seizures in patients taking drugs that lower the seizure threshold. In patients with epilepsy or those predisposed to seizures, the drug should be prescribed only for vital indications.

Tramadol has a low potential for dependence development. However, with prolonged use, the development of habituation, physical and mental dependence is possible. In patients with a tendency to abuse drugs or with drug dependence, treatment with tramadol should be carried out only in the presence of direct indications, for a short time and under constant medical supervision. Tramadol is not used as a substitute in patients with opioid dependence. Tramadol does not suppress morphine withdrawal symptoms, although it is an opioid agonist.

Effect on ability to drive vehicles and operate machinery

During the treatment period, the patient should refrain from all activities requiring increased attention and speed of psychomotor reactions (including driving a car, working at a machine), because the drug can cause a rather strong decrease in the ability to concentrate and slow down the speed of psychomotor reactions.

Overdose

Symptoms from fainting to unconsciousness (coma); epileptic seizures; miosis; vomiting; cardiovascular collapse; drop in blood pressure; palpitations (tachycardia); constriction or dilation of the pupils; difficulty breathing up to arrest.

Treatment emergency measures are applied. It is necessary to ensure airway patency (aspiration!), maintain respiration and cardiovascular activity depending on the symptoms. It is necessary to cleanse the stomach by mechanically inducing vomiting or lavage.

Tramadol is poorly eliminated by hemodialysis and hemofiltration. Therefore, performing only these procedures for overdose therapy is ineffective.

Tramadol is an opiate agonist. The opioid effects of tramadol can be stopped with morphine antagonists (e.g., naloxone). Seizures occurring at toxic doses can be eliminated with drugs from the benzodiazepine group (diazepam).

Drug Interactions

With simultaneous use of Tramal retard with other drugs that have a depressant effect on the CNS (including tranquilizers or hypnotics), as well as with ethanol, an increase in the side effects of tramadol is possible.

With simultaneous or prior administration of cimetidine (an inhibitor of liver microsomal enzymes), the absence of drug interaction with tramadol is possible.

With simultaneous or prior administration of carbamazepine (an inducer of liver microsomal enzymes), a decrease in the intensity or duration of the analgesic effect of tramadol is possible.

With simultaneous use of tramadol with analgesics of the agonist/antagonist group of opioid receptors (i.e., with buprenorphine, nalbuphine, pentazocine), the analgesic effect of the pure agonist may theoretically decrease (combined use is not recommended).

Tramadol can induce seizures and increase the seizure potential of selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotic drugs, and other agents that lower the seizure threshold. Drugs that inhibit the CYP3A4 isoenzyme, such as ketoconazole and erythromycin, may slow down the metabolism of tramadol (N-demethylation) and the metabolism of the active O-demethylated metabolite.

Storage Conditions

The drug belongs to the list of potent substances of the Permanent Committee for Drug Control of the Ministry of Health of the Russian Federation.

The drug should be stored at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.